Of the more than 600,000 acute ischemic strokes treated annually in the United States, 98% of patients receive no acute therapy. Patients with co-morbid vascular diseases, like diabetes and uncontrolled hypertension, have worse outcomes and have historically been underrepresented in preclinical studies. Long-term recovery is limited by the brain's inherent plasticity and ability to actively remodel after injury. The brain vasculature is undoubtedly a key component of recovery and therapeutic strategies that are vascular protective are likely to promote better function. The facilitation of natural recovery mechanisms, especially when cerebral ischemia is layered on preexisting vascular compromise, has great promise as a therapeutic strategy. The objective of this application is to further elucidate the mechanisms involved in vascular protection after cerebral ischemia. The central hypothesis for the proposed research is that neurovascular protection after cerebral ischemia and reperfusion can be achieved by optimization of oxidative stress and activation of remodeling. We plan to achieve this objective through the following three specific aims: Aim #1: Determine the contribution of oxidative stress and MMP modulation to the beneficial effects of angiotensin antagonism on experimental ischemic stroke outcome. Aim #2: Determine the extent to which premorbid vascular damage impacts the neurovascular protective effects of angiotensin antagonism after acute ischemic stroke. Aim #3: Determine whether reperfusion is essential for optimal vascular protection with candesartan after cerebral ischemia We will achieve these aims using normotensive, hypertensive and hyperglycemic rat models of temporary cerebral ischemia, continuous BP monitoring via telemetry, laser Doppler flowmetry, BP lowering and pharmacologic MMP and oxidative stress modulation. In addition, we will employ MMP zymography, and quantitative measures of microvascular integrity and oxidative damage using ELISA and immunoblotting and a sensitive battery of neurobehavioral tests at 3, 7 and 30 days. Lastly, we will use brain microvascular endothelial cell culture studies. At the completion of 12 experiments over 5 years, we expect that changes in oxidative stress and MMP activity will contribute to the vascular protection afforded by angiotensin blockade in the acute stroke period. We expect that the presence of prior hypertension, hyperglycemia, endogenous vascular protectors and the method and timing of treatment in relation to reperfusion status will be important in the ultimate degree of neurovascular damage. This is important because it will provide impetus and guidance for a clinical trial to improve outcome of human stroke patients. PUBLIC HEALTH RELEVANCE: Most stroke patients recover some brain function in the long-term but not enough to return to normal. Development of treatments that protect the blood vessels during a stroke may promote functional recovery. This project will determine the mechanisms of vascular protection after stroke and develop a medication treatment likely to work in stroke patients.